Prosthetic implants in arthroplasty, such as artificial knee and hip implants, typically involve the articulation of either a metal or ceramic ball shaped component, which is typically part of one half of a joint, against a polymer, such as UHMWPE, which is typically the other half of a joint, and is in the shape of a concave receptacle for receiving the articulation of the ball shaped component. More than a decade ago, it was discovered that exposure of the UHMWPE to ionizing radiation crosslinks the material and results in dramatically improved wear resistance. In contrast, the ionizing radiation also results in chain scission of the polymer chains and the creation of long-lived free radicals in the material. If these free radicals are not extinguished, they react with oxygen and result in oxidation of the polymer and subsequent degradation of the mechanical and tribological properties. To extinguish the free radicals, a post-irradiation heat treatment is commonly conducted.
Heating the crosslinked polymer above the melting temperature (i.e., re-melting) has been shown to extinguish all of the measurable free radicals in the crosslinked material and stabilize it against oxidation. On the other hand, re-melting also results in a decrease in crystallinity because the reduced mobility of the crosslinked chains inhibits the folding of the chains into crystalline lamella, which results in decreased yield and ultimate tensile strengths.
Alternatively, the crosslinked polymer can be heated to a temperature below the melting temperature (i.e., sub-melt annealing). Because the larger crystalline lamella are not melted during sub-melt annealing, the crystallinity is typically either maintained or increased, which typically maintains or improves the yield strength and leads to less of a decease in the ultimate tensile strength of the resultant material. In contrast, the choice of a sub-melt heat treatment leaves a measurable amount of free radicals in the unmelted crystalline regions of the material that can migrate out and oxidize with time.
As a result of these trade-offs, a method of stabilizing the highly crosslinked UHMWPE against oxidation without compromising the mechanical properties is desirable.
The blending of a UHMWPE resin with an antioxidant has been used to negate the need for a post-irradiation heat treatment and the subsequent trade-offs inherent to those methods. This approach blends a single antioxidant with the resin, and the blend is then consolidated by standard techniques, such as by compression molding or ram extrusion. This consolidated blend is then exposed to ionizing radiation to crosslink the material and improve the wear resistance. The blended antioxidant operates as a free-radical scavenger and interrupts the oxidation pathway by readily donating a hydrogen (H) atom to the damaged polymer chain and, in turn, taking on the free radical to form a stable free radical that it does not react with oxygen. Because a post-irradiation heat treatment may not be necessary for the removal of free radicals with this particular method, the mechanical properties are not degraded to the same extent.
On the other hand, there are two problems inherent to this blending method. First, each antioxidant molecule is capable of donating a finite number of hydrogen atoms/quenching or extinguishing a finite number of free radicals. For example, it has been theorized that each vitamin E molecule is capable of quenching two free radicals. As a result, the consumption of the antioxidant during the scavenging of free radicals could limit the effective time of protection against oxidation. For example, if the concentration of the antioxidant is too low, all of the free-radical-quenching ability could be consumed prior to the extinguishing of all of the free radicals, which would result in remaining free radicals that could react with oxygen and cause oxidation. From this prospective, it is preferable to have a high concentration of antioxidant to insure that all of it is not consumed prior to the capture of all of the free radicals and to maximize the long-term oxidation resistance. On the other hand, increasing the concentration of the antioxidant beyond a certain limit can result in a supersaturation that can cause elution or diffusion of the antioxidant out of the polyethylene. The result of this elution could be undesirable interactions of the antioxidant with the human body or depletion of the antioxidant remaining at the surfaces of the material.
Second, the improved wear resistance of the irradiated polymer is dependent upon the generation of free radicals by ionizing radiation and the subsequent combination of the free radicals to form chemical bonds (i.e., crosslinks) between polymer chains. The presence of an antioxidant during irradiation scavenges some of these free radicals and results in an undesired inhibition of crosslinking. As a result, higher irradiation doses are necessary to produce an equivalent level of wear resistance compared to an antioxidant-free polymer. As a consequence of increasing the irradiation dose to overcome the inhibition of crosslinking, the ductility and the toughness of the crosslinked material decrease even further. From this prospective, it is preferable to minimize the concentration of antioxidant to minimize the inhibition of crosslinking and the necessary irradiation dose to achieve a given wear resistance.
U.S. Pat. Nos. 7,431,874 and 7,498,365, each patent herein incorporated by reference, disclose a method to avoid these problems with blending. According to this method, the UHMWPE is consolidated and irradiated prior to the introduction of vitamin E (Vit E) into the material through diffusion. Because the material does not contain an antioxidant at the time of irradiation, there is no inhibition of crosslinking. Because inhibition is not a concern, the concentration of Vit E in the polymer can be increased to insure that there is a more than adequate amount of antioxidant to quench all of the existing free radicals and provide long-term oxidation resistance.
The negative aspects of this diffusion method are related to the time and expense necessary to diffuse a sufficient quantity of Vit E into the material and homogenize the concentration throughout the component. In addition, the higher concentrations of Vit E typically utilized in this process lead to a large concentration gradient, which could result in elution or diffusion of the Vit E out of the polyethylene and depletion of the antioxidant at the surface.
The combination of synergistic antioxidants and their effects on free-radical quenching and antioxidant “regeneration” or “recycling” has been considered in the past, but never related to medical uses, including in medical prostheses. For example, it has been demonstrated in the literature that the regeneration of Vit E takes place in vivo through chemical reactions with other molecules such as ascorbic acid (vitamin C). As a result of this interaction, the Vit E molecule is “recharged” and can theoretically quench 2 more free radicals. This process could proceed ad infinitum to provide long-term oxidation resistance with a low concentration of an antioxidant. Similar in-vivo regeneration of curcumin by a synergistic molecule has been theorized based on oncology research. In the polymeric sciences, the combinations of Vit E with a phosphate antioxidant or Vit E with polyhydric alcohol both reduce changes in color and promote higher retention of the Vit E during melt processing of polypropylene through a similar synergistic mechanism.
All of the efforts in the prior art related to UHMWPE have been to blend only one antioxidant into the UHMWPE. Moreover, EP Published Patent Application No. EP2047823 A1, for example, specifically states that “one antioxidant is preferred” for “economical and efficiency sake.” The problem with the incorporation of a single antioxidant is that it is at least partially consumed during processing, during the quenching of free radicals after processing and during use/service. As a result, the prior art composition requires a higher concentration of antioxidant to insure that there is enough antioxidant to protect the medical device against long-term oxidation for the duration of the service life. This need for a higher concentration of a single antioxidant also results in inhibition of crosslinking, the need for higher irradiation doses to achieve a given wear resistance and, ultimately, leads to degraded mechanical properties.